Our limited knowledge of the neuronal control of human airway smooth muscle is derived mostly from studies of large central airways. Based on these studies it can be concluded that the innervation of human airway smooth muscle is dominated by a cholinergic contractile system and a relaxant system that is non-adrenergic in nature. In addition, recent evidence supports the hypothesis that the human airway smooth muscle also receives noncholinergic contractile innervation. Recent studies with animal models have yielded exciting new information on the non-adrenergic, non-cholinergic innervation of the airways, and its potential regulation by inflammation. With this information and the new investigative tools available, the time is ripe to re-evaluate the nature of the innervation of human airways. The objective of the present proposal is to critically investigate the nature of the innervation of human central (2nd - 7th generation bronchi) and peripheral (bronchioles) airway smooth muscle. Using a multidisciplinary approach, experiments will be designed to determine the nature of the neurotransmitters involved in the non-adrenergic and noncholinergic responses in the airways, the regional distribution of contractile and relaxant innervation along the airway tree, and the regulation of the relaxant and contractile innervation by specific mediators known to be present in the airways during inflammatory reactions. The hypothesis that vasoactive intestinal peptide (or related peptides) and/or nitric oxide mediate the non-adrenergic relaxation and that tachykinins released from capsaicin-sensitive nerves mediate the non-cholinergic contractions will be examined using new pharmacological tools including specific antibodies to the putative transmitters, novel nitric oxide synthase inhibitors and selective tachykinin receptor agonists and antagonists. In parallel with these studies, experiments will be carried out on the innervation of the guinea pig airways so that the validity of this animal as a model for the innervation of human airways can be objectively evaluated. The proposal provides for a systematic characterization of the innervation of human central and peripheral airways. The information gained from these studies will begin to address the long range goal of understanding the contribution of the peripheral nervous system to pulmonary physiology and pathophysiology.